Bipolar Disorder is a common, often severe mental illness. Family, twin, and adoption studies have demonstrated that genes are the major determinant of individual risk for the disorder, but as in other common disorders, the identification of these genes has proven to be a significant challenge. In collaboration with 10 academic centers across the United States, we have recruited a large sample of families in which at least 2 siblings suffer from bipolar disorder or related mood disorders. To date, some 750 such families, containing over 3200 individuals, have been collected, the largest sample ever to participate in a genetic study of bipolar disorder. All research participants have undergone a diagnostic interview and provided a blood sample for DNA analysis. Genetic linkage studies have been performed using molecular markers evenly spaced across all chromosomes. These studies suggest that regions on chromosomes 8, 6, 13, 17, 18, and 22 may contain genes that contribute to bipolar disorder in these families. Ongoing work is aimed at identifying the actual genes involved. Single nucleotide polymorphisms are being used to identify small chromosomal regions that are overrepresented in people with bipolar disorder. This work has so far identified the genes G72/G30 on chromosome 13, LARGE on chromosome 22, and an as-yet-unnamed gene on chromosome 18 as the sites of genetic variation that increase risk for bipolar disorder in some people. Related basic research aims to characterize the ways in which single nucleotide polymorphisms vary in groups across populations. This research has shown that patterns of long-range variation tend to mirror short-range variation within the same chromosomal region. This finding supports earlier reports that such patterns tend to be driven by regional differences in recombination rates. Related clinical research is aimed at identifying clinical features of mood disorders that, while familial, tend to cluster in some families but not others. The goal is to identify highly familial clinical sub-groups of bipolar disorder that may be more strongly related to particular genes or genetic variants. So far we have found that many clinical features of bipolar are highly familial, while the clinical features of hypomania (a form of non-incapacitating mood elevation), psychosis (hallucinations or delusions), and frequency of illness episodes tend to cluster in particular families. Earlier we showed that families in which hypomania was clustered were most strongly linked to chromosome 18. Now it has been shown that families in which psychosis clusters are most strongly linked to chromosomes 13 and 22. This is of particular interest since these same chromosomal regions have been shown to harbor genes contributing to schizophrenia, in which nearly everyone with the disorder suffers from psychosis. Related collaborative projects are aimed at investigating genetic variation in genetic components of the hypothalamic-pituitary-adrenal axis, important in the stress response; dysbindin, a gene implicated in risk for schizophrenia; and the gene encoding the serotonin transporter, an important component of the neuronal signaling that may mediate risk for mood and anxiety disorders.